M. Manning et al., Nature, 308 652 (1984) and U.S. Pat. No. 4,469,679 have disclosed that the terminal glycine unit at the 9-position of certain vasopressin-like antagonists can be removed or replaced by L or D-Ala, Ser or Arg without necessarily affecting binding at vasopressin receptors.
U.S. Pat. Nos. 4,481,194 and 4,481,193 disclose that removing proline at position 7 or both proline and glycine at positions 7 and 9 from the structures of vasopressin antagonists gives compounds which retain substantial, but somewhat reduced, antagonist activity.
The vasopressin-like compounds of this invention have structures which are distinguished over those of the prior art in that the side chain contains both a basic amino acid and a carboxamido-containing amino acid as side chain units attached, directly or through a proline unit to a disulfide VSP-like ring. The carboxamido group is at a position other than the preferred amido at the C-terminus. Thusly, the compounds of this invention have a receptor site-seeking side chain which contains two potential sites for binding. These are a basic site such as that in Arg or Lys as well as an internal carboxamido site such as that in Gln or Asn. The resulting compounds are potent vasopressin antagonists.
In the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form. In certain structural formulas, the thio members of the Pmp, Tmp and Cys units are added for clarity.
Certain of the peptide art designations used herein are the following: Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; Tmp, .beta.-mercapto-.beta.,.beta.-cyclotetramethylenepropionic acid; Tyr(Alk), O-alkyltyrosine; Phe(Alk), 4-alkylphenylalanine; Gln, glutamic acid amide or glutamine; Tyr, tyrosine; Phe, phenylalanine; Val, valine, Ile, isoleucine; Lys, lysine; Arg, arginine; Asn, asparagine; Tos, tosylate; BHA, benzhydrylamine; DMAP, 4-dimethylaminopyridine; DIEA, diisopropylethylamine; HF, hydrogen fluoride; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; Boc, t-butyloxycarbonyl; Z, benzyloxycarbonyl; VSP, vasopressin; HOBT, hydroxybenzotriazole; ACM, acetamidomethyl. The critical glutamine or asparagine units are also written as Glu(NH.sub.2) or Asp(NH.sub.2).
"Alk" represents a lower alkyl of 1-4 carbons. For example, these may be optionally attached to the 4-oxygen substituent of a tyrosine unit or to the p-position of a phenylalanine which may be present at unit position 2. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl. Ethyl is preferred. When the term, "vasopressin", is used, it means L-arginine vasopressin (AVP) unless otherwise modified.